RESUMO
INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting in lung and liver disease with a great clinical variability. MicroRNAs have been identified as disease modifiers; therefore miRNA deregulation could play an important role in disease heterogeneity. Members of miR-320 family are involved in regulating of multiple processes including inflammation, and have potential specific binding sites in the 3'UTR region of SERPINA1 gene. In this study we explore the involvement of miR-320c, a member of this family, in this disease. METHODS: Firstly in vitro studies were carried out to demonstrate regulation of SERPINA1 gene by miR-320. Furthermore, the expression of miR-320c was analyzed in the blood of 98 individuals with different AAT serum levels by using quantitative PCR and expression was correlated to clinical parameters of the patients. Finally, HL60 cells were used to analyze induction of miR-320c in inflammatory conditions. RESULTS: Overexpression of miR-320 members in human HepG2 cells led to inhibition of SERPINA1 expression. Analysis of miR-320c expression in patient's samples revealed significantly increased expression of miR-320c in individuals with pulmonary disease. Additionally, HL60 cells treated with the pro-inflammatory factor lipopolysaccharide (LPS) showed increase in miR-320c expression, suggesting that miR-320c responds to inflammation. CONCLUSION: Our findings demonstrate that miR-320c inhibits SERPINA1 expression in a hepatic cell line and its levels in blood are associated with lung disease in a cohort of patients with different AAT serum levels. These results suggest that miR-320c can play a role in AAT regulation and could be a biomarker of inflammatory processes in pulmonary diseases.
Assuntos
Pneumopatias , MicroRNAs , Deficiência de alfa 1-Antitripsina , alfa 1-Antitripsina , Regiões 3' não Traduzidas , Humanos , Inflamação/genética , Pulmão , Pneumopatias/genética , MicroRNAs/genética , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/genéticaRESUMO
INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting in lung and liver disease with a great clinical variability. MicroRNAs have been identified as disease modifiers; therefore miRNA deregulation could play an important role in disease heterogeneity. Members of miR-320 family are involved in regulating of multiple processes including inflammation, and have potential specific binding sites in the 3'UTR region of SERPINA1 gene. In this study we explore the involvement of miR-320c, a member of this family, in this disease. METHODS: Firstly in vitro studies were carried out to demonstrate regulation of SERPINA1 gene by miR-320. Furthermore, the expression of miR-320c was analyzed in the blood of 98 individuals with different AAT serum levels by using quantitative PCR and expression was correlated to clinical parameters of the patients. Finally, HL60 cells were used to analyze induction of miR-320c in inflammatory conditions. RESULTS: Overexpression of miR-320 members in human HepG2 cells led to inhibition of SERPINA1 expression. Analysis of miR-320c expression in patient's samples revealed significantly increased expression of miR-320c in individuals with pulmonary disease. Additionally, HL60 cells treated with the pro-inflammatory factor lipopolysaccharide (LPS) showed increase in miR-320c expression, suggesting that miR-320c responds to inflammation. CONCLUSION: Our findings demonstrate that miR-320c inhibits SERPINA1 expression in a hepatic cell line and its levels in blood are associated with lung disease in a cohort of patients with different AAT serum levels. These results suggest that miR-320c can play a role in AAT regulation and could be a biomarker of inflammatory processes in pulmonary diseases.
RESUMO
INTRODUCTION AND OBJECTIVE: REDAAT, the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency, was set up in order to improve knowledge of this disease. This study is an evaluation of the registry and an analysis of its patient population. METHODS: The registry has a database hosted on the website www.redaat.es. It collects clinical and functional data on patients with PiSZ, ZZ phenotypes and other rare variants. RESULTS: Thanks to the collaboration of 124 physicians, the registry currently contains information on 511 individuals from 103 healthcare centers. Of these 511, 348 (74.2%) are Pi*ZZ homozygotes, and 100 (19.5%) are Pi*SZ heterozygotes. More cases are seen in tertiary level hospitals. A total of 81% of the cases have respiratory disease, and a lower proportion of AATD cases were detected by family screening or liver disease. Follow-up data are available for 45% of the cases, and 35% received alpha-1 antitripsin replacement therapy. CONCLUSIONS: The REDAAT registry is a useful tool for obtaining quality information about this minority disease in routine clinical practice conditions, although it is difficult to obtain follow-up data, and the representativeness of the sample included cannot be determined.
Assuntos
Sistema de Registros , Deficiência de alfa 1-Antitripsina/epidemiologia , Adulto , Idoso , Bases de Dados Factuais , Terapia de Reposição de Enzimas , Feminino , Genótipo , Geografia Médica , Humanos , Masculino , Pessoa de Meia-Idade , Espanha/epidemiologia , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/terapiaRESUMO
The effect of hereditary alpha-1 antitrypsin (AAT) deficiency can manifest clinically in the form of chronic obstructive pulmonary disease (COPD). AAT deficiency (AATD) is defined as a serum concentration lower than 35% of the expected mean value or 50 mg/dl (determined by nephelometry). It is associated in over 95% of cases with Pi*ZZ genotypes, and much less frequently with other genotypes resulting from combinations of Z, S, rare and null alleles. A systematic qualitative review was made of 107 articles, focusing mainly on an active search for AATD in COPD patients and intravenous (iv) treatment with AAT. On the basis of this review, the consultant committee of the Spanish Registry of Patients with AATD recommends that all COPD patients be screened for AATD with the determination of AAT serum concentrations, and when these are low, the evaluation must be completed with phenotyping and, on occasions, genotyping. Patients with severe AATD COPD should receive the pharmacological and non-pharmacological treatment recommended in the COPD guidelines. There is enough evidence from large observational studies and randomized placebo-controlled clinical trials to show that the administration of iv AAT reduces mortality and slows the progression of emphysema, hence its indication in selected cases that meet the inclusion criteria stipulated in international guidelines. The administration of periodic infusions of AAT is the only specific treatment for delaying the progression of emphysema associated with AATD.
Assuntos
Terapia de Reposição de Enzimas/métodos , Doença Pulmonar Obstrutiva Crônica/etiologia , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , alfa 1-Antitripsina/uso terapêutico , Ensaios Clínicos como Assunto , Método Duplo-Cego , Medicina Baseada em Evidências , Testes Genéticos , Genótipo , Humanos , Infusões Intravenosas , Metanálise como Assunto , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema de Registros , Sociedades Médicas , Espanha/epidemiologia , Resultado do Tratamento , alfa 1-Antitripsina/sangue , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/epidemiologiaRESUMO
INTRODUCTION: The present study intends to describe the characteristics of patients diagnosed with severe alpha-1 antitrypsin deficiency (AATD) in Spain, to observe the rate of decline in forced expiratory volume in 1 second (FEV1) with and without substitutive therapy, and to identify factors associated with a rapid rate of decline in FEV1. METHOD: A retrospective study of the evolution of individuals with AATD was carried out based on data collected from the Spanish registry. The primary response variable was the annual rate of decline in FEV1, calculated using the baseline and last postbronchodilator FEV1 values in an endpoint analysis. RESULTS: 303 patients with severe AATD and Pi ZZ phenotype were identified. Follow-up spirometric data were collected for 117 subjects. Being a smoker or ex-smoker versus never smoker (odds ratio [OR]=10.31; 95% confidence interval (CI)=1.8-58.8; p=0.008) and having a higher baseline postbronchodilator FEV1 (% predicted) (OR=1.03; 95% CI=1.005-1.06; p=0.018) were independently associated with a more rapid rate of decline in FEV1. There was also a trend towards a relationship between low body mass index (BMI) and a greater rate of deterioration in lung function (OR=1.14; 95% CI=0.98-1.33; p=0.085). CONCLUSION: Being a smoker or ex-smoker, greater baseline lung function, and low BMI were the main risk factors associated with an accelerated rate of decline in FEV1. This finding warrants the close observation of younger patients with a better-preserved FEV1.